Meta-Biol

• Pathways

Chloroquine (CQ) and hydroxychloroquine (HCQ) are diprotic weak bases that can exist in both protonated and unprotonated forms. Unprotonated CQ or HCQ can diffuse freely and rapidly across the membranes of cells and organelles to acidic cytoplasmic vesicles (late endosomes and lysosomes). Agents that have this ability are known as lysosomotropic agents. Once protonated, CQ2+ or HCQ2+ are trapped in the acidic lumen of these vesicles. This leads to an irreversible accumulation of CQ or HCQ in acidic vesicles to concentrations as much as 100 fold over cytosolic ones and to an elevation of vesicle pH due to trapping of H+ ions by CQ or HCQ. Thus, CQ analogues interfere with endosomal and lysosomal acidification, which in turn inhibits proteolysis, chemotaxis, phagocytosis and antigen presentation. As a result, cells are not able to proceed with endocytosis, exosome release and phagolysosomal fusion in an orderly manner (Foley & Tilley 1998, Yang & Shen 2020). In vitro, these endosomal acidification fusion inhibitors block cellular infection by a clinical isolate of SARS-CoV-2 (Wang et al. 2020, Hu et al. 2020).